AUTHOR=Ruggiero Alessandra , Pascucci Giuseppe Rubens , Cotugno Nicola , Domínguez-Rodríguez Sara , Rinaldi Stefano , Tagarro Alfredo , Rojo Pablo , Foster Caroline , Bamford Alasdair , De Rossi Anita , Nastouli Eleni , Klein Nigel , Morrocchi Elena , Fatou Benoit , Smolen Kinga K. , Ozonoff Al , Di Pastena Michela , Luzuriaga Katherine , Steen Hanno , Giaquinto Carlo , Goulder Philip , Rossi Paolo , Levy Ofer , Pahwa Savita , Palma Paolo , the EPIICAL Consortium , Cotton Mark , Barnabas Shaun , Puthanakit Thanyawee , Kuhn Louise , Yates Andrew , Violari Avy , Otwombe Kennedy , Vaz Paula , Lain Maria Grazia , Nampossa Tacilta , Naniche Denise , Fernandez-Luis Sheila , Lopez Elisa , Peay Holly , Spyer Moira , Calvez Vincent , Marcelin Anne-Genevieve , Munoz Maria Angeles , Dalzini Annalisa , Petrara Raffaella , Gartner Kathleen , Armas Lesley De , Rajendra Pahwa , Pallikkuth Suresh , Persaud Deborah , Chomont Nicolas , Lichterfeld Mathias , Faggion Silvia , Pena Daniel Gomez , Oletto Andrea , Nardone Alessandra , Zangari Paola , Cesare Silvia Di , Medri Chiara , Kolesova Olga , Paganin Carla , James William , Lindfors - Rossi Inger , Hassan Shrabon Samiur , Mazzetto Francesca , Akisinku Hellen , Chingandu Musakanya , Rocchi Francesca , Pepponi Ilaria , De Boer Rob J. , Schroter Juliane , Giannuzzi Viviana , Yates Andrew , Morris Sinead TITLE=Determinants of B-Cell Compartment Hyperactivation in European Adolescents Living With Perinatally Acquired HIV-1 After Over 10 Years of Suppressive Therapy JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.860418 DOI=10.3389/fimmu.2022.860418 ISSN=1664-3224 ABSTRACT=Background

Despite a successful antiretroviral therapy (ART), adolescents living with perinatally acquired HIV (PHIV) experience signs of B-cell hyperactivation with expansion of ‘namely’ atypical B-cell phenotypes, including double negative (CD27-IgD-) and termed age associated (ABCs) B-cells (T-bet+CD11c+), which may result in reduced cell functionality, including loss of vaccine-induced immunological memory and higher risk of developing B-cells associated tumors. In this context, perinatally HIV infected children (PHIV) deserve particular attention, given their life-long exposure to chronic immune activation.

Methods

We studied 40 PHIV who started treatment by the 2nd year of life and maintained virological suppression for 13.5 years, with 5/40 patients experiencing transient elevation of the HIV-1 load in the plasma (Spike). We applied a multi-disciplinary approach including immunological B and T cell phenotype, plasma proteomics analysis, and serum level of anti-measles antibodies as functional correlates of vaccine-induced immunity.

Results

Phenotypic signs of B cell hyperactivation were elevated in subjects starting ART later (%DN T-bet+CD11c+ p=0.03; %AM T-bet+CD11c+ p=0.02) and were associated with detectable cell-associated HIV-1 RNA (%AM T-bet+CD11c+ p=0.0003) and transient elevation of the plasma viral load (spike). Furthermore, B-cell hyperactivation appeared to be present in individuals with higher frequency of exhausted T-cells, in particular: %CD4 TIGIT+ were associated with %DN (p=0.008), %DN T-bet+CD11c+ (p=0.0002) and %AM T-bet+CD11c+ (p=0.002) and %CD4 PD-1 were associated with %DN (p=0.048), %DN T-bet+CD11c+ (p=0.039) and %AM T-bet+CD11c+ (p=0.006). The proteomic analysis revealed that subjects with expansion of these atypical B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Furthermore, we observed that higher levels of ABCs were associated a reduced capacity to maintain vaccine-induced antibody immunity against measles (%B-cells CD19+CD10- T-bet+, p=0.035).

Conclusion

We identified that the levels of hyperactivated B cell subsets were strongly affected by time of ART start and associated with clinical, viral, cellular and plasma soluble markers. Furthermore, the expansion of ABCs also had a direct impact on the capacity to develop antibodies response following routine vaccination.